The n e w e ng l a n d j o u r na l of
Original Article
The authors’ full names, academic de-
grees, and affiliations are listed in the
Appendix. Address reprint requests to Dr.
Regules at ­jason​.­a​.­regules​.­mil@​­mail​.­mil.
*
A complete list of members of the
rVSV∆G-ZEBOV-GP Study Group is pro-
vided in the Supplementary Appendix,
available at NEJM.org.
Drs. Regules and Beigel and Drs. Davey
and Thomas contributed equally to this
article.
A preliminary version of this article was
published on April 1, 2015, at NEJM.org.
N Engl J Med 2017;376:330-41.
DOI: 10.1056/NEJMoa1414216
Copyright © 2017 Massachusetts Medical Society.
330
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m e dic i n e
A Recombinant Vesicular Stomatitis Virus
Ebola Vaccine
J.A. Regules, J.H. Beigel, K.M. Paolino, J. Voell, A.R. Castellano, Z. Hu, P. Muñoz,
J.E. Moon, R.C. Ruck, J.W. Bennett, P.S. Twomey, R.L. Gutiérrez, S.A. Remich,
H.R. Hack, M.L. Wisniewski, M.D. Josleyn, S.A. Kwilas, N. Van Deusen, O.T. Mbaya,
Y. Zhou, D.A. Stanley, W. Jing, K.S. Smith, M. Shi, J.E. Ledgerwood, B.S. Graham,
N.J. Sullivan, L.L. Jagodzinski, S.A. Peel, J.B. Alimonti, J.W. Hooper, P.M. Silvera,
B.K. Martin, T.P. Monath, W.J. Ramsey, C.J. Link, H.C. Lane, N.L. Michael,
R.T. Davey, Jr., and S.J. Thomas, for the rVSV∆G-ZEBOV-GP Study Group*​​
A BS T R AC T
BACKGROUND
The worst Ebola virus disease (EVD) outbreak in history has resulted in more than
28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials
of an attenuated, replication-competent, recombinant vesicular stomatitis virus
(rVSV)–based vaccine candidate designed to prevent EVD.
METHODS
We conducted two phase 1, placebo-controlled, double-blind, dose-escalation tri-
als of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain
of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all)
were consecutively enrolled into groups of 13. At each site, volunteers received one
of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU],
20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites re-
ceived a second dose at day 28. Safety and immunogenicity were assessed.
RESULTS
The most common adverse events were injection-site pain, fatigue, myalgia, and
headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1.
The rates of adverse events and viremia were lower after the second dose than
after the first dose. By day 28, all the vaccine recipients had seroconversion as as-
sessed by an enzyme-linked immunosorbent assay (ELISA) against the glycopro-
tein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies
against ZEBOV glycoprotein were higher in the groups that received 20 million
PFU or 100 million PFU than in the group that received 3 million PFU, as assessed
by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after
dose 1 significantly increased antibody titers at day 56, but the effect was dimin-
ished at 6 months.
CONCLUSIONS
This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccina-
tion, rVSV viremia occurred frequently but was transient. These results support
further evaluation of the vaccine dose of 20 million PFU for preexposure prophy-
laxis and suggest that a second dose may boost antibody responses. (Funded by
the National Institutes of Health and others; rVSV∆G-ZEBOV-GP ClinicalTrials.gov
numbers, NCT02269423 and NCT02280408.)
n engl j med 376;4 nejm.org  January 26, 2017
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 Recombinant Vesicular Stomatitis Virus Ebola Vaccine
T
he worst Ebola virus disease (EVD)
outbreak in recorded history has resulted
in more than 28,000 cases and 11,000 re-
ported deaths.1 Although the primary strategy to
stop the transmission of Ebola remains the iden-
tification and isolation of contacts and the use of
appropriate personal protective equipment, the
development of a safe and efficacious vaccine
would provide an important public health tool.
Numerous Ebola virus vaccine candidates are in
preclinical development, and some have pro-
ceeded to human trials.2-5
An Ebola virus vaccine candidate based on an
attenuated, replication-competent, recombinant
vesicular stomatitis virus (rVSV) has shown prom-
ise in preclinical studies. The vaccine candidate
(rVSV-ZEBOV) is genetically engineered to replace
the VSV glycoprotein with the glycoprotein from
a Zaire strain of Ebola virus (ZEBOV). Vaccina-
tion induces replication of viral particles similar
to VSV but expressing the ZEBOV surface glyco-
protein. ZEBOV glycoprotein is responsible for
receptor binding and membrane fusion between
ZEBOV and host target cells and the induction of
functional antibodies, including neutralizing
antibodies.6
Preclinical testing of rVSV-ZEBOV supports its
potential efficacy. The rVSV-ZEBOV vaccine has
been shown to be attenuated in normal and im-
munocompromised nonhuman primates in safety
and immunogenicity studies.7,8 Multiple studies
in cynomolgus macaques have shown that a sin-
gle administration of the vaccine confers a high
level of protection against lethal challenge.9,10
Various methods of vaccine delivery (oral, intra-
nasal, or intramuscular) have shown protective
efficacy in animal models.11
On the basis of this preclinical experience, we
conducted phase 1, double-blind, placebo-con-
trolled, dose-escalation studies of rVSV-ZEBOV
at two locations in the United States: the Walter
Reed Army Institute of Research (WRAIR), in
Silver Spring, Maryland, and the National Insti-
tutes of Health (NIH) Clinical Center, in Bethesda,
Maryland. Although the studies were designed
as two independent studies, the assessments and
data collections were largely harmonized. The
WRAIR evaluated a single-dose strategy, where-
as the NIH evaluated a homologous, two-dose
regimen administered at study days 0 and 28.
Safety and humoral-immunogenicity data through
day 180 after vaccination, generated by the same
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laboratories for both trials, are presented here
for the three vaccine dose levels (3 million
plaque-forming units [PFU], 20 million PFU, and
100 million PFU) that were under consideration
for human use. On the basis of the data pre-
sented here and additional clinical and preclini-
cal data, the rVSV-ZEBOV vaccine (at the dose of
20 million PFU) was selected for inclusion in the
Partnership for Research on Ebola Vaccines in
Liberia (PREVAIL) trial (ClinicalTrials.gov num-
ber, NCT02344407), a phase 3 efficacy study in
Guinea,12 and the phase 3 Sierra Leone Trial to
Introduce a Vaccine against Ebola (STRIVE,
NCT02378753).
Me thods
Vaccine
The rVSV-ZEBOV vaccine candidate is a live at-
tenuated recombinant virus consisting of the
VSV strain Indiana, with the glycoprotein of the
ZEBOV Kikwit 1995 strain replacing the gene for
the VSV envelope glycoprotein. The resultant rVSV
construct contains surface ZEBOV glycoprotein
that exhibits a narrower host-cell tropism in vitro
than wild-type VSV, as well as considerable at-
tenuation of replication.13 A 2015 analysis esti-
mated a 3.4% nucleotide divergence (approxi-
mately 1.6% amino acid divergence) between the
ZEBOV Kikwit 1995 strain and a limited number
of genomic sequences for the currently circulat-
ing strain,14 although no conclusions regarding
the effect on immunogenicity can be made.
The vaccine was developed by the Public
Health Agency of Canada, licensed to BioProtec-
tion Systems (NewLink Genetics), and most re-
cently sublicensed to Merck, which is responsi-
ble for ongoing research and development. The
sponsor of the investigational new drug (IND)
application, BioProtection Systems, was involved
in discussions of the study design and in the
study monitoring and statistical analysis; it also
provided the vaccine candidate. The vaccine,
which was manufactured according to current
Good Manufacturing Practices, was formulated
with recombinant human serum albumin and
tris(hydroxymethyl)aminomethane buffer and was
dispensed in a vial containing 100 million PFU
per milliliter (lot number 003 05 13). Normal
saline was used as a diluent by the study phar-
macists to formulate the doses of 3 million PFU
or 20 million PFU.
331
 The n e w e ng l a n d j o u r na l
Volunteers and Study Design
Both trials were phase 1, double-blind, placebo-
controlled, dose-escalation trials. The trials were
designed to assess the safety, reactogenicity, and
immunogenicity of rVSV-ZEBOV across three
dose levels: 3 million PFU, 20 million PFU, and
100 million PFU. A total of 78 healthy adult men
and women from the Washington, D.C.–Balti-
more metropolitan area were recruited accord-
ing to protocols that were approved by the in-
stitutional review board at each site. Written
informed consent was obtained from all the
volunteers before enrollment. Exclusion criteria
were active involvement in clinical care of pa-
tients; substantial contact with immunocompro-
mised populations, children 5 years of age or
younger, or animals at risk for VSV infection;
and a history of infection with filoviruses or
VSV, predisposition for exposure to filoviruses
or VSV, or previous receipt of a filovirus vaccine
or VSV-vectored vaccine. Pregnant or lactating
women and persons found to have the human
immunodeficiency virus, hepatitis B or C virus
infection, or clinically significant medical condi-
tions at screening were excluded.
Study Procedures
A total of 39 adults at each site were consecu-
tively enrolled into groups of 13 each. In each
group, 3 volunteers were randomly assigned in a
blinded manner to receive the control (saline
placebo), and 10 were assigned to receive the
rVSV-ZEBOV vaccine at a dose of 3 million PFU,
20 million PFU, or 100 million PFU. Each par-
ticipant received a 1-ml injection in the deltoid
muscle; at the NIH site, a second identical dose
was administered 28 days after the first. Volun-
teers were assessed on days 1, 3, 7, 14, and 28
after the first and (if applicable) second injection.
Data on solicited adverse events related to injec-
tion-site and systemic reactogenicity were col-
lected for 14 days after each injection. Data on
unsolicited adverse events, changes in medical
status, and concomitant medication use were
collected for 28 days after each injection. Blood
samples were obtained for assessment of safety
and immunologic end points. All the volunteers
had safety laboratory evaluations (including a
complete blood count with differential; measure-
ments of serum creatinine, alanine aminotrans-
ferase, and aspartate aminotransferase levels;
determination of the prothrombin time and
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of m e dic i n e
partial-thromboplastin time; and urinalysis [red-
cell count and levels of protein and glucose]) at
baseline and 7 days and 28 days after each injec-
tion. In addition, the WRAIR site evaluated these
laboratory variables 1 day and 3 days after in-
jection. Grading of adverse events was based on
Food and Drug Administration toxicity grading.15
Positivity for vaccine ZEBOV-glycoprotein nucleic
acid sequences was assessed in plasma, saliva,
and urine. At the WRAIR, samples were obtained
before the injection and on days 1, 3, 7, and 14
after the injection. At the NIH site, specimens
were obtained on days 3 and 7 after each injec-
tion. Further details are available in the trial
protocols, available with the full text of this ar-
ticle at NEJM.org.
rVSV-ZEBOV Surveillance by RT-PCR
A reverse-transcriptase–polymerase-chain-reaction
(RT-PCR) assay was used to measure potential
rVSV virus in the plasma, saliva, and urine,
through amplification of the Ebola Zaire glyco-
protein gene insert of the vaccine. The assay was
performed at the WRAIR. Details are provided
in the Supplementary Appendix, available at
NEJM.org.
Measurement of Antibody Responses to Ebola
Glycoprotein
The primary assays for antibody response were
an enzyme-linked immunosorbent assay (ELISA)
against the homologous Zaire–Kikwit strain
glycoprotein and a pseudovirion neutralization
assay (PsVNA) against the homologous Zaire–
Kikwit strain glycoprotein. These assays were
performed at the U.S. Army Medical Research
Institute of Infectious Diseases (see the Methods
section of the Supplementary Appendix). A lim-
ited number of samples were also tested with the
use of an ELISA against the Zaire–Mayinga
strain glycoprotein at the Vaccine Research Cen-
ter of the National Institute of Allergy and Infec-
tious Diseases, with the use of methods described
previously,16 to allow cross-vaccine comparisons
of immunogenicity.
Statistical Analysis
Statistical analyses were performed with the use
of R software, version 3.3.1. For each serologic
variable, data were summarized by assessment
day and included the geometric mean titer and
95% confidence interval, the median value, and
 Recombinant Vesicular Stomatitis Virus Ebola Vaccine

Table 1. Characteristics of the Participants at Enrollment.*

Vaccine, 3 Million PFU Vaccine, 20 Million PFU Vaccine, 100 Million PFU Placebo Overall
Characteristic (N = 20) (N = 20) (N = 20) (N = 18) (N = 78)
Sex — no. (%)
Male 13 (65) 16 (80) 15 (75) 11 (61) 55 (71)
Female 7 (35) 4 (20) 5 (25) 7 (39) 23 (29)
Age — yr 36.9 ±11.8 34.6±12.2 38.8±14.7 32.7±10.7 35.8±12.4
Race — no. (%)†
Asian 4 (20) 3 (15) 1 (5) 2 (11) 10 (13)
Black 4 (20) 7 (35) 8 (40) 4 (22) 23 (29)
White 10 (50) 10 (50) 10 (50) 12 (67) 42 (54)
Multiracial 2 (10) 0 1 (5) 0 3 (4)
Hispanic ethnic group 1 (5) 4 (20) 1 (5.0) 0 6 (8)
— no. (%)†
Body-mass index‡ 26.3±4.7 26.7±5.2 28.7±7.9 27±6.6 27±6.2

* Plus–minus values are means ±SD. There were no significant between-group differences at baseline. PFU denotes plaque-forming units.
† Race and ethnic group were self-reported.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.

minimum and maximum values. A two-sample
t-test was performed for comparison of geomet-
ric mean titers between dose levels and study
sites. A paired t-test was used for comparisons
between time points within a dose level. All
calculations and comparisons of geometric mean
titers were performed on the log10 scale.
A positive response for the Kikwit strain
ELISA was defined as a titer of 50 or more, with
titers of less than 50 assigned values of 25 for
calculation. A positive response for the PsVNA
was defined as a titer of 20 or more, with titers
of less than 20 assigned values of 10 for calcula-
tion. Seroconversion on these assays was de-
fined as a quadrupling of the titer over the
baseline value. Baseline values were subtracted
from the postvaccination values for determina-
tion of the Mayinga strain ELISA titers, as de-
scribed previously.3,4
R e sult s
Study Participants
A total of 78 volunteers (55 men [71%] and 23
women [29%]), with a mean age of 36 years
(range, 20 to 64), were enrolled in a consecutive
manner; injections were administered between
October 10, 2014, and January 6, 2015. A total of
60 volunteers were randomly assigned to receive
rVSV-ZEBOV, and 18 volunteers were randomly
assigned to receive saline placebo. At the NIH
site, all the participants received a second identi-
cal dose of vaccine 28 days after the initial dose.
All the volunteers completed the follow-up visits
that were scheduled during the 28-day windows
after vaccination; however, 4 volunteers were lost
to follow-up by the conclusion of the trial (Fig. S1
in the Supplementary Appendix). Additional de-
tails regarding the demographic characteristics
of the volunteers are provided in Table 1.
Safety
There were no deaths, serious adverse events, or
adverse events resulting in withdrawal from the
study. There was no association between vaccine
dose and the frequency or severity of adverse
events (Fig. 1, and Figs. S2 and S3 and Table S10
in the Supplementary Appendix). After a single in-
oculation of vaccine, mild-to-moderate injection-
site pain was observed in the majority of par-
ticipants. Systemic reactogenicity was transient
and, in the majority of volunteers, mild to moder-
ate in severity. Objective fever was noted in 20 of
the 60 vaccinees: 11 (18%) had grade 1 fever
(temperature range, 38.0 to 38.4°C), 7 (12%) had
grade 2 fever (temperature range, 38.5 to 38.9°C),
and 2 (3%) had grade 3 fever (temperature range,
39.0 to 40.0°C). Fever onset and frequency did
not appear to be dose-dependent (Fig. 1, and Fig.
S2 in the Supplementary Appendix); fever typically

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Grade 1 Grade 2 Grade 3

Adverse Event
Cohort 1
Cohort 2
Abdominal Pain
Cohort 3
Placebo
Cohort 1
Cohort 2
Arthralgia
Cohort 3
Placebo
Cohort 1
Cohort 2
Chills
Cohort 3
Placebo
Cohort 1
Cohort 2
Diaphoresis
Cohort 3
Placebo
Cohort 1
Cohort 2
Diarrhea
Cohort 3
Placebo
Cohort 1
Cohort 2
Fatigue
Cohort 3
Placebo
Cohort 1
Cohort 2
Fever, Objective
Cohort 3
Placebo
Cohort 1
Cohort 2
Fever, Subjective
Cohort 3
Placebo
Cohort 1
Cohort 2
Headache
Cohort 3
Placebo
Cohort 1
Injection-Site Cohort 2
Pain Cohort 3
Placebo
Cohort 1
Injection-Site Cohort 2
Swelling Cohort 3
Placebo
Cohort 1
Cohort 2
Myalgia
Cohort 3
Placebo
Cohort 1
Cohort 2
Nausea
Cohort 3
Placebo
0 10 20 30 40 50 60 70 80 90 100
Participants (%)

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 Recombinant Vesicular Stomatitis Virus Ebola Vaccine
Figure 1 (facing page). Frequency of Solicited Adverse
Events According to Cohort and Grade.
Cohort 1 received a dose of 3 million plaque-forming
units (PFU) of the vaccine, Cohort 2 a dose of 20 mil-
lion PFU, and Cohort 3 a dose of 100 million PFU. All
adverse events were assessed for relatedness to the
vaccine; events that were judged by the investigating
physicians not to be related to the vaccine are not shown.
Adverse events were graded for severity on the basis
of Food and Drug Administration toxicity grading.15
Unsolicited adverse events and laboratory adverse
events are shown in the Supplementary Appendix.
developed 12 to 24 hours after vaccination and
resolved by the end of postvaccination day 1.
One volunteer who received a dose of 3 million
PFU had grade 1 fever 7 days after vaccination
that resolved within 24 hours without develop-
ment of other symptoms.
Other commonly reported systemic symptoms
among vaccinees were headache, myalgia, and
fatigue, with typical onset 12 to 24 hours after
vaccination. Notable adverse events were unilat-
eral conjunctivitis that developed in one volun-
teer 1 day after inoculation and oral ulcers that
developed in five vaccinated volunteers 4 to 16 days
after vaccination. PCR analysis of swabs of the
affected areas (a conjunctival swab and swabs of
three of the five oral ulcers) was negative for the
Ebola glycoprotein gene insert. Three vaccinated
participants had cervical lymphadenopathy; one
of the three also reported an oral ulcer. Infec-
tious colitis developed in one participant 21 days
after vaccination; symptoms included severe ab-
dominal pain on the left side and four episodes
of mild diarrhea with blood. Computed tomog-
raphy of the abdomen at an outside hospital
showed mild thickening of the descending colon.
All conditions resolved without complications.
Among participants who received a second dose
of the vaccine, reactogenicity at the injection site
and systemic reactogenicity were less severe after
the second dose than after the first dose. A com-
plete list of solicited and unsolicited adverse
events is provided in Table S10 in the Supple-
mentary Appendix.
Safety laboratory values were generally unre-
markable, with the majority of adverse events
occurring after the first dose of vaccine. Transient
mild-to-moderate lymphopenia occurred in 24 of
60 participants, typically on day 1, with abatement
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by day 3 after vaccination. Mild-to-moderate
neutropenia, which occurred in 14 of 60 partici-
pants, was most notable on day 3 after vaccina-
tion and typically abated within 2 to 4 days. An
asymptomatic grade 2 thrombocytopenia, asso-
ciated with grade 1 lymphopenia, was noted on
day 1 after vaccination in one volunteer who re-
ceived a dose of 20 million PFU; the condition
resolved by day 7.
After a report from a phase 1 study in Geneva
of the onset of arthritis in 22% of the partici-
pants starting the second week after injection,17,18
volunteers were specifically queried about the
development of new arthralgia, arthritis, or rash
during the second week or later after vaccina-
tion. A total of 19 participants reported arthral-
gia, typically soon after vaccination. Five partici-
pants had an onset of arthralgia 7 to 14 days
after vaccination, and 3 participants had arthral-
gia that began after the second vaccination. No
clinical cases of arthritis were diagnosed.
rVSV-ZEBOV on PCR Assay
PCR results are shown in Table 2. All the vacci-
nated volunteers had detectable vaccine viremia
at the first visit after vaccination (day 1 at the
WRAIR and day 3 at the NIH). Twelve of the 60
vaccinated volunteers (20%) had viremia on day 7
after vaccination. Viremia was undetectable by
day 14 in all vaccinees tested at that time point
(30 volunteers at the WRAIR). In the group that
received a dose of 3 million PFU, there was one
positive urine sample on day 3 and one on day 7.
Across the vaccine groups, a small number of
saliva samples were PCR-positive on days 1, 3, 7,
and 14. Two subsequent saliva samples were
PCR-negative in the single volunteer who had a
positive PCR saliva sample on day 14. Cycle-
threshold values for the positive urine sample on
day 7 and saliva sample on day 14 were near the
lower limit of detection for the assay.
After administration of a second vaccine dose
at the NIH site, a single volunteer in the group
that received a dose of 100 million PFU had vi-
remia 3 days later. PCR results were otherwise
negative in blood, urine, and saliva.
ELISA for Ebola Glycoprotein
ELISA results are shown in Figure 2 and Table 3,
and Tables S1 through S4 in the Supplementary
Appendix. After a single dose of vaccine, IgG
335
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Vaccine Virus Detection by Means of Qualitative Reverse-Transcriptase–Polymerase-Chain-Reaction Assay.

Type of Specimen Day 1* Day 3 Day 7 Day 14* Day 31† Day 35†

no. of positive samples/no. of samples tested (%)

Blood
Vaccine, 3 million PFU 10/10 (100) 20/20 (100) 1/20 (5) 0/10 0/10 0/10
Vaccine, 20 million PFU 10/10 (100) 20/20 (100) 5/20 (25) 0/10 0/9 0/10
Vaccine, 100 million PFU 10/10 (100) 19/20 (95) 6/20 (30) 0/10 1/8 (12) 0/9
Urine
Vaccine, 3 million PFU 0/10 1/10 (10) 1/10 (10) 0/10 0/10 0/10
Vaccine, 20 million PFU 0/10 0/17 0/20 0/10 0/9 0/10
Vaccine, 100 million PFU 0/10 0/19 0/19 0/10 0/8 0/9
Saliva
Vaccine, 3 million PFU 0/10 2/20 (10) 0/20 0/10 0/10 0/10
Vaccine, 20 million PFU 0/10 0/19 5/20 (25) 1/10 (10) 0/10 0/10
Vaccine, 100 million PFU 1/10 (10) 0/19 1/19 (5) 0/10 0/9 0/9

* Data for days 1 and 14 are from the Walter Reed Army Institute of Research only.
† Data for days 31 and 35 (after the second dose) are from the National Institutes of Health (NIH) Clinical Center only.

responses were observed. A total of 16 of 20
volunteers (80%) who received a dose of 3 mil-
lion PFU, 19 of 20 volunteers (95%) who received
a dose of 20 million PFU, and 18 of 20 who re-
ceived a dose of 100 million PFU had undergone
seroconversion by day 14. All 60 vaccinated vol-
unteers (100%) had undergone seroconversion by
day 28. The groups that received a dose of 20 mil-
lion PFU or 100 million PFU had higher geomet-
ric titers against the Zaire–Kikwit strain than the
group that received a dose of 3 million PFU, both
on day 14 (857 and 888 vs. 283; P = 0.008 and
P = 0.02, respectively) and on day 28 (4079 and
4079 vs. 1300; P = 0.001 and P<0.001, respective-
ly). All vaccinated cohorts showed increases in
titers from day 14 to day 28; titers increased
from 283 on day 14 to 1300 on day 28 in the
group receiving a dose of 3 million PFU (P<0.001),
from 857 to 4079 in the group receiving a dose
of 20 million PFU (P<0.001), and from 888 to
4079 in the group receiving a dose of 100 mil-
lion PFU (P = 0.01)). There was no significant dif-
ference in the geometric mean titer between the
group that received a dose of 20 million PFU and
the group that received a dose of 100 million PFU.
At day 28, there were no significant differ-
ences in the geometric mean titer between the
groups that were to receive a second vaccine
dose and those that were not. All three groups
that received a second dose had increases in titers
from day 28 to day 56; titers increased from
1300 on day 28 to 4222 on day 56 in the group
that received a dose of 3 million PFU (P<0.001),
from 5198 to 7352 in the group that received a
dose of 20 million PFU (P = 0.27), and from 3676
to 11,143 in the group that received a dose of
100 million PFU (P<0.001). Among participants
who received a second dose, the geometric mean
titer was higher at day 84 than at day 28 in the
group that received a dose of 3 million PFU

Figure 2 (facing page). Antibody Responses to Ebola Glycoprotein.

Individual antibody titers as assessed at 14 and 28 days after vaccination are shown according to vaccine dose
group, as measured by an enzyme-linked immunosorbent assay (ELISA) against the Zaire–Kikwit strain glycoprotein
(Panel A) and a pseudovirion neutralization assay (Panel B). Geometric mean titers (horizontal lines) are shown for
each group and time point. Geometric mean titers from 28 days after initial vaccination through 180 days after ini-
tial vaccination are shown for the glycoprotein ELISA (Panel C) and the pseudovirion neutralization assay (Panel D).
Solid lines indicate groups that received a second dose at day 28, and dashed lines indicate groups that did not re-
ceive a second dose at day 28. In all panels, I bars indicate 95% confidence intervals.

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 Recombinant Vesicular Stomatitis Virus Ebola Vaccine

A Zaire–Kikwit Glycoprotein ELISA at 14 and 28 Days B Pseudovirion Neutralization Assay at 14 and 28 Days
5.0 5.0

4.5 4.5

4.0 4.0
Log10 Geometric Mean Titer

Log10 Geometric Mean Titer

3.5 3.5

3.0 3.0

2.5 2.5

2.0 2.0

1.5 1.5

1.0 1.0

0.0 0.0
Day 14 Day 28 Day 14 Day 28 Day 14 Day 28 Day 14 Day 28 Day 14 Day 28 Day 14 Day 28
Vaccine, Vaccine, Vaccine, Vaccine, Vaccine, Vaccine,
3 Million PFU 20 Million PFU 100 Million PFU 3 Million PFU 20 Million PFU 100 Million PFU

C Zaire–Kikwit Glycoprotein ELISA from Day 28 to Day 180

4.5

4.0
Log10 Titer

3.5

Vaccine, 3 million PFU

3.0
Vaccine, 20 million PFU
Vaccine, 100 million PFU
2.5

0.0
28 56 84 180
Day

D Pseudovirion Neutralization Assay from Day 28 to Day 180

3.5
Vaccine, 3 million PFU
3.0 Vaccine, 20 million PFU
Vaccine, 100 million PFU
2.5
Log10 Titer

2.0

1.5

1.0

0.0
28 56 84 180
Day

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 338
Table 3. Geometric Mean Antibody Titers.*

Study Group Day 14† Day 28† Day 56 Day 84 Day 180

With Second Without Second With Second Without Second With Second Without Second
Vaccination‡ Vaccination Vaccination‡ Vaccination Vaccination‡ Vaccination

geometric mean titer (95% CI)

Zaire–Kikwit glycoprotein
The

ELISA
Vaccine, 3 million PFU 283 1300 4222 2599 2986 2263 3200 2786
(150–534) (831–2034) (2478–7195) (1537–4395) (1823–4889) (1485–3449) (1878–5452) (1248–6218)
Vaccine, 20 million PFU 857 4079 7352 3733 4222 2743 3676 2540
(502–1465) (2601–6396) (4972–10,871) (2085–6682) (3269–5455) (1634–4604) (2486–5435) (1196–5396)
Vaccine, 100 million PFU 888 4079 11,143 4525 7352 3940 5572 2786
(448–1760) (2740–6070) (8143–15,248) (1933–10,597) (4972–10,871) (1501–10,343) (3339–9298) (1169–6638)
Placebo§ 29 29 30 27 31
(23–38) (23–38) (25–37) (23–32) (20–47 )
PsVNA
Vaccine, 3 million PFU 39 223 344 138 33 N/A 36 26
n e w e ng l a n d j o u r na l

(24–62) (145–342) (203–583) (74–256) (15–69) (16–81) (10–71)

The New England Journal of Medicine

of

Vaccine, 20 million PFU 47 441 653 170 47 N/A 35 23

(20–107) (236–825) (468–911) (106–275) (28–81) (17–70) (10–52)
Vaccine, 100 million PFU 127 461 669 219 90 N/A 47 46

n engl j med 376;4 nejm.org  January 26, 2017

(67–242) (312–681) (418–1071) (98–486) (47–173) (16–141) (21–103)

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

m e dic i n e

Placebo§ 10 10 10 10 10
(10-–10) (10–10) (10–10) (10–10) (10–10)

* At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received a vaccine dose of 20 million PFU or 100 million PFU than in the
group that received a dose of 3 million PFU, both as assessed by an enzyme-linked immunosorbent assay (ELISA) (4079 and 4079 vs. 1300; P = 0.001 and <0.001, respectively) and as
assessed by a pseudovirion neutralization assay (PsVNA) (441 and 461 vs. 223; P = 0.07 and P = 0.01, respectively). For the PsVNA, the day 84 analysis was performed only at the NIH

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Clinical Center. CI denotes confidence interval, and NA not applicable.
† Analyses at day 14 and day 28 include data from volunteers at both study sites (all volunteers with only one vaccination at these time points).
‡ The second vaccination was administered on day 28.
§ Volunteers in the placebo group received no vaccinations.
 Recombinant Vesicular Stomatitis Virus Ebola Vaccine
(1300 at day 28 vs. 2986 at day 84 [P = 0.02]) and
in the group that received a dose of 100 PFU
(3676 at day 28 vs. 7352 at day 84 [P = 0.02]).
Among participants who did not receive a sec-
ond dose, only the group that received a dose of
3 million PFU had significant increases in the geo­
metric mean titer from day 28 through day 84
(1300 at day 28 vs. 2599 at day 56 [P<0.001] and
1300 at day 28 vs. 2263 at day 84 [P = 0.003]). In
all three vaccinated groups, participants who re-
ceived a second vaccination had higher geomet-
ric mean titers on day 56 than those who did not
(4222 vs. 2599 in the group that received a dose
of 3 million PFU [P = 0.16], 7352 vs. 3733 in the
group that received a dose of 20 million PFU
[P = 0.04], and 11,143 vs. 4525 in the group that
received a dose of 100 million PFU [P = 0.04]). At
the 180-day follow-up, there was no significant
difference in geometric mean titers between the
groups that received a second dose of vaccine
and the groups that received a single dose.
PsVNA Titers
Results with respect to neutralizing antibody ti-
ters against the Zaire–Kikwit strain glycoprotein
are shown in Figure 2 and Table 3, and Table S5
through S8 in the Supplementary Appendix. Af-
ter a single vaccination, all groups had neutral-
izing antibodies by day 28, in a dose-dependent
manner. The geometric mean titer in the group
that received a dose of 100 million PFU was sig-
nificantly higher than in the group that received
a dose of 3 million PFU both on day 14 (127 vs.
39 [P  = 0.004]) and on day 28 (461 vs. 223
[P = 0.01]). All three dose groups had significant
increases in the geometric mean titer from day
14 to day 28; the titer increased from 39 on day
14 to 223 on day 28 in the group that received a
dose of 3 million PFU (P<0.001), from 47 to 441
in the group that received a dose of 20 million
PFU (P<0.001), and from 127 to 461 in the group
that received a dose of 100 million PFU (P<0.001).
At day 28, there were no significant differ-
ences in the geometric mean titer between the
groups that were to receive a second vaccine
dose and those that were not. Groups that re-
ceived a second dose of vaccine had an initial
trend of increased geometric mean titers during
the month after revaccination (222 at day 28 vs.
344 at day 56 in the group that received a dose
of 3 million PFU [P = 0.08], 415 vs. 653 in the
group that received a dose of 20 million PFU
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[P = 0.33], and 476 vs. 669 in the group that re-
ceived a dose of 100 million PFU [P = 0.19]).
However, this trend was reversed in titers mea-
sured 2 months after revaccination (222 at day
28 vs. 33 at day 84 in the group that received a
dose of 3 million PFU [P<0.001], 415 vs. 47 in
the group that received a dose of 20 million PFU
[P = 0.003], and 476 vs. 90 in the group that re-
ceived a dose of 100 million PFU [P<0.001]).
Vaccine groups that did not receive a second
dose had a decrease in neutralizing antibody
responses from day 28 to 56 (223 vs. 138 in the
group that received a dose of 3 million PFU
[P = 0.06], 468 vs. 170 in the group that received
a dose of 20 million PFU [P = 0.008], and 447 vs.
219 in the group that received a dose of 100 mil-
lion PFU [P = 0.02]). At the 180-day follow-up,
there was no significant difference in neutraliz-
ing antibody responses between the groups that
received a second dose of vaccine and the groups
that received a single dose.
Discussion
Both a single and a second administration of the
rVSV-ZEBOV Ebola vaccine candidate elicited an
antibody response without any safety concerns
being identified. In 60 healthy adults, the vac-
cine candidate had an acceptable safety profile
across all dose concentrations. The most common
side effects were injection-site pain, myalgia,
fatigue, headache, subjective fever, and chills.
Immunogenicity as measured by means of IgG
ELISA was concordant with antibody responses
measured with the use of a functional (neutral-
ization) assay, and the IgG ELISA results sug-
gested a dose response, especially between the
group receiving a dose of 3 million PFU and the
groups receiving higher doses, with little differ-
ence between the group receiving a dose of 20
million PFU and the group receiving a dose of
100 million PFU. Although transient arthralgia
was noted in a minority of volunteers, clinical
arthritis, which was reported in another clinical
trial of the vaccine candidate, was not observed
at the WRAIR or NIH site. These data supported
selection of 20 million PFU as the dose for clini-
cal end-point trials (PREVAIL trial, the Guinea
study, and STRIVE) in West Africa. In the Guinea
study, this dose recently showed high protec-
tive efficacy with the use of a ring vaccination
strategy.12
339
 The n e w e ng l a n d j o u r na l of m e dic i n e

Transient rVSV viremia was detected after im-
munization, recapitulating the experience de-
scribed previously in nonhuman primates.19 The
clinical symptoms associated with this viremia
included fever and appeared to peak and then
decrease in the 12 to 36 hours after vaccination.
Overall, safety laboratory values were subclinical
and unremarkable. Moderate asymptomatic de-
clines in leukocyte subsets (e.g., lymphopenia and
neutropenia) were noted during the first 3 days
after vaccination and resolved rapidly. The data
from the clinical trials presented herein are
consistent with the preclinical experience and,
combined with the established attenuation of the
vaccine vector, provide further support for the
safety of rVSV vectors.2,13,20
The immunoprotective profile that is required
for the prevention of EVD remains largely un-
known, and mechanistic correlates of protection
remain undefined. Successful protection in the
nonhuman primate model has been shown with
various vaccine candidates, with imputation of
both cellular and humoral immune responses as
correlates of protection.21,22 In the nonhuman pri-
mate challenge model, antibody response, prin-
cipally IgG, has been the strongest immune
correlate of protection associated with the rVSV-
ZEBOV vaccine candidate.10,23,24 Although the
Kikwit strain ELISA has become the primary
readout, examination of the Mayinga-strain gly-
coprotein titers (Table S9 in the Supplementary
Appendix) suggests that the rVSV-ZEBOV vaccine
candidate produces cross-strain glycoprotein-
specific antibodies similar to those described for
the chimpanzee adenovirus 3 vaccine candidate.3
Neutralizing antibody assays typically have been
difficult to correlate with outcomes in studies in
animals involving EVD, but the functional assay
used for the reported trials showed a strong as-
sociation with protection of nonhuman primates
across multiple vaccine platforms and warrants
further investigation as a correlate of protec-
tion.24-27
A second dose of vaccine was less reactogenic
and induced less viremia than the primary dose.
Although a two-dose regimen was associated
with a short-term advantage with respect to the
magnitude of the humoral response, we did not
observe a significant difference in the day 180
titer between the one-dose and two-dose vaccine
regimens. The vaccine candidate has already
shown efficacy in populations living in regions
in which EBV is endemic, but the immunologic
profiles presented here suggest that two doses
of vaccine administered within a short time
frame may provide increased short-term benefit.5
In addition, however, strategies such as longer
intervals between doses could be pursued to
improve the longer-term immunologic profile.
Such work would need to go hand-in-hand with
assessment of efficacy in the animal model and
validation of the presented immune correlates.
The results reported here support the safety,
acceptable side-effect profile, and immunoge-
nicity of up to two doses of the rVSV-ZEBOV
vaccine and encourage further investigation of
this vaccine candidate. Most promising are the
robust immune responses after a single dose of
the vaccine and the rapid onset of immunity,
which could be particularly useful in outbreak
interventions. Although we found short-term in-
creases in humoral immunity after a second dose
at the 1-month interval, it remains unknown
whether this regimen will translate to improved
clinical efficacy. Strategies to better understand
and improve immunogenicity, including assess-
ment of dose and regimen alterations, a longer
duration of follow-up, and cross-strain protection
against other Ebola viruses, could be pursued.
The views expressed are those of the authors and should not be
construed as official or representing the positions of the Depart-
ments of the Army, Navy, or Defense or the National Institutes of
Health (NIH). The content of this article does not necessarily re-
flect the views or policies of the Department of Health and Human
Services, nor does mention of trade names, commercial products,
or organizations imply endorsement by the U.S. Government.
Supported by the Intramural Research Programs of the Na-
tional Institute of Allergy and Infectious Diseases, NIH; the Na-
tional Cancer Institute, NIH (contract no. HHSN261200800001E);
the Defense Threat Reduction Agency; and the Joint Vaccine Ac-
quisition Program.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

Appendix
The authors’ full names and academic degrees are as follows: Jason A. Regules, M.D., John H. Beigel, M.D., Kristopher M. Paolino,
M.D., Jocelyn Voell, R.N., M.S., Amy R. Castellano, L.P.N., Zonghui Hu, Ph.D., Paula Muñoz, B.S., James E. Moon, M.D., Richard C.
Ruck, M.D., Jason W. Bennett, M.D., Patrick S. Twomey, M.D., Ramiro L. Gutiérrez, M.D., Shon A. Remich, M.D., Holly R. Hack, M.S.,
Meagan L. Wisniewski, Ph.D., Matthew D. Josleyn, M.S., Steven A. Kwilas, Ph.D., Nicole Van Deusen, B.S., Olivier Tshiani Mbaya, M.D.,
Yan Zhou, Ph.D., Daphne A. Stanley, M.S., Wang Jing, M.S., Kirsten S. Smith, Ph.D., Meng Shi, M.A., Julie E. Ledgerwood, D.O.,
Barney S. Graham, M.D., Nancy J. Sullivan, Ph.D., Linda L. Jagodzinski, Ph.D., Sheila A. Peel, M.S.P.H., Ph.D., Judie B. Alimonti, Ph.D.,

340 n engl j med 376;4 nejm.org  January 26, 2017

The New England Journal of Medicine

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 Recombinant Vesicular Stomatitis Virus Ebola Vaccine

Jay W. Hooper, Ph.D., Peter M. Silvera, Ph.D., Brian K. Martin, Ph.D., Thomas P. Monath, M.D., W. Jay Ramsey, M.D., Ph.D., Charles J.
Link, M.D., H. Clifford Lane, M.D., Nelson L. Michael, M.D., Ph.D., Richard T. Davey, Jr., M.D., and Stephen J. Thomas, M.D.
The authors’ affiliations are as follows: the Walter Reed Army Institute of Research (J.A.R., K.M.P., A.R.C., J.E.M., R.C.R., J.W.B.,
P.S.T., S.A.R., H.R.H., M.S., L.L.J., S.A.P., N.L.M., S.J.T.) and Naval Medical Research Center (R.L.G.), Silver Spring, Leidos Biomedical
Research, Frederick National Laboratory for Cancer Research (J.H.B., W.J.), and the U.S. Army Medical Research Institute of Infectious
Diseases (M.L.W., M.D.J., S.A.K., N.V.D., K.S.S., J.W.H., P.M.S.), Frederick, and the National Institute of Allergy and Infectious Dis-
eases (NIAID) (J.V., Z.H., P.M., H.C.L., R.T.D.) and NIAID Vaccine Research Center (O.T.M., Y.Z., D.A.S., J.E.L., B.S.G., N.J.S.),
Bethesda — all in Maryland; the Public Health Agency of Canada, Ottawa (J.B.A.); and BioProtection Systems–NewLink Genetics, Ames,
IA (B.K.M., T.P.M., W.J.R., C.J.L.).

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